Leukocyte infiltration in response to bacterial invasion can be a contributor to tissue damage (Gupta et al. (1996b) Kidney Int. 49:26-33). Leukocyte infiltration in response to pathogen infection does not result in pathological changes in the tissue as long as reactive oxygen species (ROS) formed by leukocytes and macrophages stay within the phagocytic vacuoles inside of these cells. However, the general mechanism of anti-pathogen response (in the case of infection-induced inflammation) involves generation of ROS by neutrophil and macrophage NADPH oxidases (Sanmun et al. (2009) Am. J. Physiol. Cell. Physiol. 297:C621-631). The extracellular release of ROS becomes damaging and leads to tissue injury and dysfunction (Mundi et al. (1991) Infect. Immun, 59:4168-4172). In addition to ROS release, the inflammatory response also involves release of cytokines, eicosanoids, complement activation and mobilization of destructive enzymes (Nassar and Badr (1998) J. Nephrol. 11:177-184), and mononuclear cells (MNCs) i.e., macrophages and monocytes, play a role in such tissue damage (Friedewald and Rabb (2004) Kidney Int. 66:486-491). For example, it has been demonstrated that fibrosis, a hallmark of tissue damage, is much less pronounced when the level of monocyte infiltration in the kidney is low.
Acute Pyelonephritis (APN) is an example of a disorder initially caused by a bacterial infection and in which the inflammatory response to the infection leads to kidney injury and dysfunction. Although the kidney and urinary tract are normally germ-free, during their lifetime, about 40% of women and 12% of men experience urinary tract infections (UTIs) (O'Hanley, (1996) In: Urinary Tract Infections: Molecular Pathogenesis and Clinical Management (Mobley et al., eds), (Washington, D.C.: ASM Press), pp. 405-425). APN is a potentially life-threatening complication of UTI which occurs when infection progresses to the upper urinary tract. The uropathogen most frequently associated with this disease is the pyelonephritogenic subset of Escherichia coli, which is implicated in up to 85% of both complicated and uncomplicated UTIs (Hill et al. (2005) Obstet. Gynecol. 105:18-23).
Pharmacological treatment of APN is used to manage the oxidative stress response, thereby providing a therapeutic effect in preventing renal pathologies (Aydogdu et al. (2006) Gin. Exp. Pharmacol. Physiol. 33:119-124; Koyner et al. (2008) Nephron. Exp. Nephrol. 109:e109-117; Polo-Romero et al. (2004) Ren. Fail. 26:613-618; Rodrigo et al. (2004) Nephrol. Dial. Transplant. 19:2237-2244; Sadeghi et al. (2008) Pediatr. Nephrol. 23:1503-1510; Singh et al. (2004) Toxicology 201:143-151). However, treatment is complicated by the diversity of ROS generating mechanisms, and their differential contribution to host defense from infection and collateral tissue damage. Mitochondria and NADPH oxidases are the two principle sources of ROS, although their relative contribution to inflammatory pathologies is not well defined.
Thus, what is needed are improved methods of treating, or inhibiting, or preventing the ROS-release-related tissue damage resulting from inflammation accompanying certain disorders.